Phosphodiesterase inhibitors

Abstract

The invention related to compounds for formula I useful for inhibiting phosphodiesterase-4.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is N or CH in the following ring: 
 
       
         
           
           
               
               
           
         
         X is CH, CH 2 , O, S, N or NH in the following ring: 
       
       
         
           
           
               
               
           
         
       
       wherein
 each R 1  and R 2  is separately alkyl, haloalkyl, cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl, where the alkyl, cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl can be covalently linked to the oxygen via a lower alkyl; and 
 R 3  is phenyl substituted with 1-3 substituents independently chosen from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH-alkyl, N-dialkyl, NH-acyl, NH-aryl, OCO-alkyl, SCO-alkyl, SOH, SO-alkyl, SO 2 H, SO 2 -alkyl, SO 2 NH 2 , SO 2 NH-alkyl, SO 2 N-dialkyl, CF 3 , F, Cl, Br, and I groups, such that R 3  comprises an O-alkyl substituent at the 2-position. 
 
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , having one of the following formulas: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  and R 2  is separately alkyl, haloalkyl, cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl, where the alkyl, cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl can be covalently linked to the oxygen via a lower alkyl; and 
 R 3  is phenyl substituted with 1-3 substituents independently chosen from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH-alkyl, N-dialkyl, NH-acyl, NH-aryl, OCO-alkyl, SCO-alkyl, SOH, SO-alkyl, SO 2 H, SO 2 -alkyl, SO 2 NH 2 , SO 2 NH-alkyl, SO 2 N-dialkyl, CF 3 , F, Cl, Br, and I groups, such that R 3  comprises an O-alkyl substituent at the phenyl 2-position. 
 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein X is S or CH in the following ring: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein R 3  is dimethoxyphenyl. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the R 1  and R 2  groups are each lower alkyl, cycloalkyl or heterocycloalkyl, where the cycloalkyl, or heterocycloalkyl can be covalently linked to the oxygen via a lower alkyl. 
     
     
         9 . The compound of  claim 8 , wherein R 1  and R 2  lower alkyl groups are each independently methyl or ethyl. 
     
     
         10 . The compound of  claim 1 , wherein the at least one of R 1  and R 2  is a lower alkyl group that is substituted with 1-3 halide atoms. 
     
     
         11 . The compound of  claim 1 , having any of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 X is N or CH in the following ring: 
 
       
         
           
           
               
               
           
         
         X at other locations is CH; and 
         each R 1  and R 2  is separately alkyl, haloalkyl, cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl, where the alkyl, cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl can be covalently linked to the oxygen via a lower alkyl. 
       
     
     
         12 . A composition comprising a carrier and at least one compound of  claim 1 . 
     
     
         13 . The composition of  claim 12 , wherein the carrier is a pharmaceutically acceptable carrier. 
     
     
         14 . The composition of  claim 12 , wherein the compound of  claim 1  is present in the composition in a therapeutically effective amount. 
     
     
         15 . A method for inhibiting phosphodiesterase-4 in a mammalian cell, comprising administering to the mammal an effective amount of the composition of  claim 13  to thereby inhibit phosphodiesterase-4 in the mammal. 
     
     
         16 . The method of  claim 15 , wherein the effective amount is effective for inhibiting at least 30% of the phosphodiesterase-4. 
     
     
         17 . The method of  claim 15 , wherein the effective amount is effective for inhibiting at least 50% of the phosphodiesterase-4. 
     
     
         18 . The method of  claim 15 , wherein the effective amount is effective for inhibiting at least 60% of the phosphodiesterase-4. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 15 , wherein the effective amount of the composition comprises about 0.0001 mg/kg to about 500 mg/kg of a compound of  claim 1 . 
     
     
         21 . The method of  claim 19 , wherein phosphodiesterase-4 is inhibited within a cell in a mammal to treat any one of the following diseases or disorders: inflammation, acute airway disorders, chronic airway disorders, inflammatory airway disorders, allergen-induced airway disorders, bronchitis, allergic bronchitis, bronchial asthma, emphysema, chronic obstructive pulmonary disease, dermatoses, proliferative dermatoses, inflammatory dermatoses, allergic dennatosis, psoriasis (vulgaris), toxic eczema, allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and widespread pyodermias, endogenous and exogenous acne, acne rosacea, proliferative, inflammatory and allergic skin disorders, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, arthritis, AIDS, multiple sclerosis, graft versus host reaction, allograft rejection, shock, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, Crohn's disease, ulcerative colitis, inflammatory bowel disease, allergies, allergic rhinitis, sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps, cardiac insufficiency, erectile dysfunction, kidney colic, ureter colic in connection with kidney stones, diabetes, diabetes insipidus, cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia, depression, psychosis, arteriosclerotic dementia or a combination thereof. 
     
     
         22 - 23 . (canceled) 
     
     
         24 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is N or CH in the following ring: 
 
       
         
           
           
               
               
           
         
       
       X is CH, CH 2 , O, S, N or NH in the following ring: 
       
         
           
           
               
               
           
         
         each R 1  cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl, where the cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl can be covalently linked to the oxygen via a lower alkyl; 
       
       each R 2  is alkyl, haloalkyl, cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl, where the cycloalkyl, cycloalkylhalo, heterocycloalkyl, or aryl can be covalently linked to the oxygen via a lower alkyl; and
 R 3  is aryl substituted with 1-3 substituents independently chosen from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, OH, O-alkyl, SH, S-alkyl, NH 2 , NH-alkyl, N-dialkyl, NH-acyl, NH-aryl, OCO-alkyl, SCO-alkyl, SOH, SO-alkyl, SO 2 H, SO 2 -alkyl, SO 2 NH 2 , SO 2 NH-alkyl, SO 2 N-dialkyl, CF 3 , F, Cl, Br, and I groups. 
 
     
     
         25 . A compound according to  claim 24 , wherein:
 R 3  is dimethoxyphenyl; and   X is S or CH in the following ring: